Scleroderma or systemic sclerosis (SSc) is a multi-system disease with high morbidity and mortality whose[unreadable] etiology and pathogenesis are unknown. The pathological picture in SSc includes widespread cutaneous[unreadable] and visceral fibrosis, obliterative small vessel disease, and autoimmune phenomena. Increasingly, evidence[unreadable] is being accumulated that SSc is a complex and heterogeneous disorder in which several (or many) genes[unreadable] interact, perhaps also with environmental factors. In this proposal, we will use a functional genomics or[unreadable] systems biology approach to complement genetic association studies in identifying susceptibility/expression[unreadable] genes, genetic networks and molecular pathways involved in the pathogenesis of SSc. In addition to casecontrol[unreadable] association studies of candidate genes using SNP genotyping in several large SSc cohorts, diseaserelated[unreadable] gene expression profiles using DNA microarrays of SSc skin biopsies, cultured fibroblasts, and[unreadable] peripheral blood cells (and subsets thereof) will be determined and analyzed using novel modeling methods.[unreadable] In addition, selected genes in important pathways so identified will undergo gene silencing using RNA[unreadable] interference (RNAi) in order to determine their effects and relative merits for potential therapeutic intervention[unreadable] in SSc. Such a "functional genomics" approach will integrate DNA variation, gene expression, and protein[unreadable] function/interactions into a more comprehensive picture of molecular mechanisms, whose understanding will[unreadable] lead to new and more rational/targeted approaches to therapy, cure, or prevention for this devastating[unreadable] disease.[unreadable] Lay language: This study aims to better understand the genetic causes of scleroderma and determine the[unreadable] genetic and cellular pathways contributing to its different complicating features. Blood and skin biopsy[unreadable] samples from patients with scleroderma will be studied using modern genetic typing and "genomic"[unreadable] technologies to identify such pathways, how they cause disease, and where interference may halt the[unreadable] process. Such studies will increase our knowledge of the mechanisms causing scleroderma and will lead to[unreadable] better medical treatments, cure or prevention.